NDUFS4 regulates cristae remodeling in diabetic kidney disease

Author:

Mise KokiORCID,Long Jianyin,Galvan Daniel L.ORCID,Ye Zengchun,Fan Guizhen,Sharma Rajesh,Serysheva Irina I.ORCID,Moore Travis I.ORCID,Jeter Collene R.,Anna Zal M.,Araki Motoo,Wada JunORCID,Schumacker Paul T.,Chang Benny H.,Danesh Farhad R.ORCID

Abstract

AbstractThe mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Springer Science and Business Media LLC

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